Carboxylic Acid Derivatives
and
Nucleophilic Acyl
Substitution Reactions
McMurray Text
Chapter 21
Carboxylic Acid Derivatives
O
R
O
OH
R
X
Acid Halide
O
O
O
R
O
R
OR'
Ester
R
O
R'
Acid Anhydride
NH2
Amide (1°)
Nomenclature
Acid Halides (Acyl Halides)
Change “–ic acid” in the parent carboxylic
acid to “–yl” followed by the halide.
O
H3C
O
Cl
Cl
acetyl chloride
(from acetic acid)
Cl
O
hexanedioyl chloride
O
H3CH2CHC
CH3
(from hexanedioic acid)
Cl
2-methylbutanoyl chloride
(from 2-methylbutanoic acid)
Nomenclature
Symmetrical Acid Anhydrides
Change “acid” in the parent carboxylic acid
to “anhydride.”
O
O
O
acetic anhydride
(from 2 acetic acids)
O
O
O
butanoic anhydride
(from 2 butanoic acids)
Nomenclature
Unsymmetrical Acid Anhydrides
Name the two acids alphabetically and
change “acid” to “anhydride.”
O
O
O
O
O
O
H
acetic benzoic anhydride
ethanoic methanoic anhydride
Nomenclature
Esters
Name R group bonded to O, followed by
replacing “–ic acid” in the parent acid with “–ate.”
O
O
O
ethyl acetate
O
O
methyl butanoate
EtO
O
OEt
diethyl propanedioate
O
O
isopentyl acetate
Nomenclature
Amides
1° amides: Change “–oic acid” (IUPAC) or “-ic acid”
(common) in the parent acid to “–amide.”
O
acetamide
NH2
2° and 3° amides: First identify the substituent groups
(preceded by “N-”)and then the parent amide.
O
O
N
H
N-Methylacetamide
H
N
N,N-Dimethylformamide
Nucleophilic Acyl Substitution
O
O
+
R
Lv
O
Nu
R
Lv
+
Nu
tetrahedral
intermediate
R
Nu
Lv
Reactivity of Acid Derivatives:
Steric Effects
O
R
C
R
R
O
<
H
C
R
R
O
<
H
C
H
R
O
<
H
C
H
H
Reactivity toward nucleophilic substitution
Most Hindered
Least Hindered
Reactivity of Acid Derivatives:
Electronic Effects
O
O
O
NH2
Amide
O
<
<
<
R
O
R
OR'
Ester
R
O
R'
Acid Anhydride
R
X
Acid
Halide
Reactivity toward nucleophilic substitution
Carbonyl carbon
least electrophilic
Carbonyl carbon
most electrophilic
Nucleophilic Acyl Substitution Rxns
O
Alcoholysis
OR1
R
H-
R1OH
R
R
Aminolysis
NH2
NH3
R
Grignard
Reagent
O
O
O
Reduction
Y
R1MgX
H
O
R1MgX
R1
R
O
Hydrolysis
H2O
H-
R
OH
Preparation of Acyl Halides
O
SOCl2
O
R
R
OH
PBr3
Cl
O
R
Br
Note: Acid fluorides are extremely reactive and
require different preparation methods.
Preparation of Anhydrides
O
O
Heat
2 R
R
OH
O
O
+ H2O
R
Carboxylic acid
Anhydride
Carboxylic
acid
O
COOH
COOH
Heat
+ H2O
O
Cyclic Anhydride
O
Succinic anhydride
Succinic acid
O
O
O
NaOH
R
OH
R
R1
O-Na+
O
Cl
R
O
O
R1
Mixed Anhydride
Preparation of Esters
Fischer Esterification
O
R
O
OH
OR1
R
R1OH
H+
O
R
H+
O
OH
R
+ H2O
H
OH
OH
R
O
HO H
R1OH
O
-H2O
R
H
OR1
O
H
H
R1
O
H
R1
R
O
HO
H
O
R
OR1
Note: If one uses labeled alcohol, the
label is retained in the product.
Preparation of Amides
 No simple method for the preparation of
amides from carboxylic acids!
 Amides from acids discussed in 26.10
Interconversion of Derivatives
 All acid derivatives can be converted to
carboxylic acids.
 A derivative can
be converted to a less
reactive derivative.
 A derivative cannot
be converted to a
more reactive derivative.
 Anhydrides can be converted to esters
and amides, but not into acid halides.
Interconversion
 Lecture 2 (with review)
Reactivity of Acid Derivatives:
Electronic Effects
O
O
O
NH2
Amide
O
<
<
<
R
O
R
OR'
Ester
R
O
R'
Acid Anhydride
R
X
Acid
Halide
Reactivity toward nucleophilic substitution
Carbonyl carbon
least electrophilic
Carbonyl carbon
most electrophilic
Nomenclature
 Acid chloride: “-yl
chloride”
 Anhydride: “anhydride”
 Ester: “-ate”
 Amide: “amide”
O
H3C
O
O
Cl
acetyl chloride
(from acetic acid)
isopentyl acetate
Nucleophilic Acyl Substitution
O
O
+
R
Lv
O
Nu
R
Lv
+
Nu
tetrahedral
intermediate
R
Nu
Lv
Interconversion
Acid Halide Hydrolysis
O
R
O
Cl
OH2
R
OH2
Cl
OH
O
O
Acid
R
OH
R
O
H
A base such as pyridine, triethylamine, or NaOH
is used to remove the HCl that is formed.
H
Acid Halides into Anhydrides
Acid chloride/carboxylate reaction useful for preparing
either symmetrical or unsymmetrical anhydrides.
O
O
O
OH
NaOH
O-Na+ H3C
O
Cl
O
O
CH3
Mixed Anhydride
Acid Halide Alcoholysis
OH
O
+
+
Cl
NH
Cl
O
+
O
Ester
N
Acid Halide Aminolysis
O
C
Cl
2 NH3
O
C
H
O
C
2 H N
Cl
CH3
2 H N
CH3
Cl
NH2
+ NH4Cl
Formation of a primary amide
Benzamide
Benzoyl Chloride
O
C
O
C
O
C
H
N
CH3
N
CH3
+ CH3NH3Cl Formation of a secondary amide
+ H N ClH CH3
Formation of a tertiary amide
O
NH
Cl
O
Cl
N
H
m-toluyl chloride
O
N
3° amide!
O
N
H
Cl
N,N-diethyl-m-toluamide
(DEET)
Acid Halide Reduction
R
O
C
Cl 1
OR
Ester
R
O
C
1. LAH
2.
H3O+
R1MgX
Cl
Grignard
Reagent
R
O
C
LAH
R
H
Aldehyde
R
O
C
R1
Ketone
H
H
C
OH
Primary alcohol
R1MgX
1
R1 R
C
OH
R
Tertiary alcohol
Acid Halides into Ketones
Gilman reagent: R2CuLi
(lithium diorganocopper)
O
C
Cl
(CH3)2CuLi
O
C
CH3
No overoxidation as opposed to Grignard reactions!
Note: Carboxylic acids, esters, acid anhydrides, and amides
do not react with Gilman reagents.
Acid Anhydride Reactions
 Less
reactive than acid chlorides, but react
in a similar fashion…
 Hydrolysis

React with water to form carboxylic acids
 Alcoholysis

React with alcohols to form esters
 Aminolysis

React with amines to form amides
 Reduction

React with LiAlH4 to form 1° alcohols
Acid Anhydride
Alcoholysis:
Ester
Aminolysis:
Amide
Ester Hydrolysis
base-catalyzed hydrolysis
(saponification)
O
CH2O C (CH2)16CH3
O
CHO C (CH2)16CH3
O
CH2O C (CH2)16CH3
CH2OH
NaOH
H2O
CH2OH
Triglyceride
R
O
C
OR1
Glycerol
R
O
C
OR1
OH
OH
CHOH
O
+ 3 H3C(CH2)16 C ONa
R
O
C
OH +
Sodium Stearate
R1O
R
O
C
O
Soap
+ R1OH
Ester Hydrolysis
acid-catalyzed hydrolysis
(reverse Fischer Esterification)
R
O
C
OR1
R
H
R
O
C
H
OH
O
H
O
C
O
H
OR1
R
H
O
C
O
H
OR1
H
H
H
R
O
C
OH
Acid
+ H3O+
R
O
C
H
O
O H
H
R1
R
O
C
H
OH
+ R1OH
Ester Aminolysis
Esters react with ammonia and
with 1° and 2° amines to form amides.
O
+
Ph
OEt
NH3
O
Ph
+ EtOH
NH2
Ester Reduction
R
O
C
OR1
Ester
R
O
C
OR
Cl
1. LAH
2. H3O+
R1MgX
Grignard
Reagent
R
O
C
LAH
R
H
Aldehyde
R
O
C
R1
Ketone
H
H
C
OH
Primary alcohol
R1MgX
1
R
R
C
OH
R
1
Tertiary alcohol
Amide Hydrolysis
R
O
C
1. HO
NH2
2.
H3O+
R
O
C
Acid
OH
Amide Reduction
 Amides into Amines using LiAlH4
 Product of reduction is an amine, not an
alcohol as with the other acid derivatives
R
R
O
C
O
C
NH2
H
2. H3O+
R
OAlH3
NH2
H
C
R
NH2
NH2
Primary amine
H
C
H
H
1. LAH
N
C
R
H
H
H
H
R
H
C
NH2
Primary amine
Nucleophilic Substitution Rxns Summary
Product
Starting
Material
Acid
Chloride
Acid
Anhydride
Carboxylic
Acid
Ester
Amide
Acid Chloride
-
Rxn
Rxn
Rxn
Rxn
Acid Anhydride
0
-
Rxn
Rxn
Rxn
Carboxylic Acid
Rxn
Rxn
-
Rxn
Rxn
Ester
0
0
Rxn
-
Rxn
Amide
0
0
Rxn
0
-
0 = No reaction